The Hippo signaling pathway is an emerging growth control and tumor suppressor pathway that is conserved between Drosophila and mammals. Study of the Hippo signaling pathway in mammalian systems has only recently begun in earnest and many outstanding questions remain. In the proposed research we will focus on three areas pertinent to Hippo pathway signaling in development and tissue homeostasis, focusing on the mouse liver as a model system. First, the role of Hippo signaling in regulation of embryonic stem and progenitor proliferation, differentiation, and self-renewal will be explored. Second, we will define cell autonomous and cell non-autonomous roles for Hippo signaling in regulation of adult liver stem and progenitor cell proliferation, differentiation, and self-renewal. Finally, we will tke advantage of our recently completed in vivo transposon-based mutatagenesis screen to identify novel Hippo pathway components and pathways that integrate with Hippo signaling to regulate liver cell growth.